IAPS BLOCK APOPTOTIC EVENTS INDUCED BY CASPASE-8 AND CYTOCHROME-C BY DIRECT INHIBITION OF DISTINCT CASPASES

Inhibitor of apoptosis (IAP) gene products play an evolutionarily cons erved role in regulating programmed cell death in diverse species rang ing from insects to humans. Human XIAP, cIAP1 and cIAP2 are direct inh ibitors of at least two members of the caspase family of cell death pr oteases: caspase-3 and caspase-7, Here we compared the mechanism by wh ich IAPs interfere with activation of caspase-3 and other effector cas pases in cytosolic extracts where caspase activation was initiated by caspase-8, a proximal protease activated by ligation of TNF-family rec eptors, or by cytochrome c, which is released from mitochondria into t he cytosol during apoptosis, These studies demonstrate that XIAP, cIAP 1 and cIAP2 can prevent the proteolytic processing of pro-caspases -3, -6 and -7 by blocking the cytochrome c-induced activation of procaspa se-9, In contrast, these IAP family proteins did not prevent caspase-8 -induced proteolytic activation of pro-caspase-3; however, they subseq uently inhibited active caspase-3 directly, thus blocking downstream a poptotic events such as further activation of caspases, These findings demonstrate that IAPs can suppress different apoptotic pathways by in hibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis.